Oxidated derivatives of triazolylpurines useful as ligands of the adenosine a2a receptor and their use as medicaments

ABSTRACT

The present invention relates to new triazolyl purine derivatives of formula (I), processes for their preparation, and to pharmaceutical compositions containing them for the treatment of neurological disorders or cerebral ischaemia for which inhibition of adenosine A2A receptor will result at improving the health state of a patient.

RELATED APPLICATIONS AND INCORPORATION BY REFERENCE

This application is a Divisional of U.S. application Ser. No. 13/257,750filed Nov. 14, 2011, which is a National Stage Entry ofPCT/EP2010/053554 filed Mar. 18, 2010, which published as PCTPublication No. WO 2010/106145 on Sep. 23, 2010, which claims benefit ofEuropean Patent Application EP 09155690.2 filed Mar. 20, 2009.

The foregoing applications, and all documents cited therein or duringtheir prosecution (“appin cited documents”) and all documents cited orreferenced in the appin cited documents, and all documents cited orreferenced herein (“herein cited documents”), and all documents cited orreferenced in herein cited documents, together with any manufacturer'sinstructions, descriptions, product specifications, and product sheetsfor any products mentioned herein or in any document incorporated byreference herein, are hereby incorporated herein by reference, and maybe employed in the practice of the invention. More specifically, allreferenced documents are incorporated by reference to the same extent asif each individual document was specifically and individually indicatedto be incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to new triazolyl purine derivatives,processes for their preparation, and to pharmaceutical compositionscontaining them for the treatment of neurological disorders for whichinhibition of adenosine A_(2A) receptor will result at improving thehealth state of a patient.

BACKGROUND OF THE INVENTION

Adenosine A₂ is an endogenous modulator, which among other effectsmediates a general depression of the central nervous system,vasodilatation and inhibition of platelet aggregation.

Adenosine receptors represent a subclass (P1) of the group of purinenucleotide and nucleoside receptors known as purinoreceptors. Up to now,four subtypes of adenosine receptors are known (i.e., A₁, A_(2A), A_(2B)(of high and low affinity) and A₃ receptors). Adenosine receptors areall coupled to G-proteins; A₁ and A₃ subtypes are associated withinhibitory G-proteins and the A_(2A) and A_(2B) subtypes are associatedwith stimulatory G-proteins. Activation of the A₁ and A₃ receptorscauses inhibition of adenylate cyclase and phospholipase C, whichinhibits neurotransmission. The A₁ receptors are highly expressed in thebrain, especially in the hippocampus, thalamus, cerebellum and cortexcompared to the A₃ receptors which are moderately expressed in thebrain. Activation of the A_(2A) and A_(2B) receptors causes activationof adenylate cyclase and phospholipase C, resulting in the stimulationof neurotransmission. A_(2A) receptors are co-expressed in the brainwith dopamine D2 receptors, especially in the striatum, olfactorytubercle and nucleus accumbens and are involved in neurodegenerativepathologies.

A_(2a) receptors are densely distributed in the central nervous system(striatum, nucleus accumbens and olfactory tubercles) where they play animportant role in the regulation of mood and motor activity (Poulsen, S.A., et al., Bioorg. Med. Chem., 1998, 6, 619; Ongini, E., et al., TrendsPharmacol. Sci., 1996, 17, 364). Parkinson's disease has been treatedfor more than thirty years by dopamine replacement strategies (Cotzias,G. C., et al., N. Engl. J. Med., 1969, 280, 337). However, becauselong-term use of dopamine-replacing agents is associated with severelydisabling side effects, most notably dyskinesia (Chase T. N., Neurology,1998, 50, S17-S25), non-dopaminergic treatments as monotherapies werejudged as a promising strategy to treat such a disease (Brotchie, J. M.,Curr. Opin. Neurol., 1997, 10, 340). Moreover, some scientific evidencesalso suggest that increased synthesis of adenosine A_(2a) receptors instriatopallidal pathway neurons is associated with the development ofdyskinesias following long-term levodopa therapy in Parkinson's disease(Calon, F., et al., Brain, 2004, 127, 1075; Xiao, D., et al., J.Neurosci., 2006, 26, 52, 13548). A_(2A) antagonists, in association witha low dose of L-DOPA, displayed antiparkinsonian activity similar tothat produced by a full dose of L-DOPA without exacerbating abnormalmotor side effects (Tronci E., et al. Eur J. Pharmacol., 2007, 566, 94;Jenner P., Expert Opin. Investig. Drugs, 2005, 14, 6, 729).

Adenosine has also been implicated in numerous other pathologies such asepilepsy, cerebral ischaemic preconditioning, sleep and immune reactionwithin the brain (Brundege, J. M., et al., Adv. Pharma., 1997, 39, 353).

Imidazopyrimidine derivatives of formula A as antidiabetic compounds aredisclosed in U.S. Pat. No. RE39112 E (Eisai Co., Ltd.).

94% of the latter compounds (223 out of 237 exemplified compounds)present a fluoro-containing phenyl moiety as R³ group and/or a tertiaryalcohol within the R¹ radical, suggesting that those moieties constitutean important feature to confer the activity.

A patent (EP1412354) filed by the Applicant disclosedtriazolylimidazopyridine and triazolylpurine derivatives endowed ofanti-psychotic properties. However, none of the compounds of the presentinvention were neither disclosed nor suggested.

DESCRIPTION OF THE INVENTION

The invention provides novel compounds of formula I, or a hydrate orsolvate thereof and compositions that include such compounds endowedwith adenosine A_(2a) inhibiting properties:

-   -   R¹═ is C₁-C₆ linear or branched alkyl;    -   R² is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴, R⁶ and R⁸ are at any occurrence independently H, hydroxyl or        ═O with the meaning of carbonyl;    -   R⁵, R⁷ and R⁹ are at any occurrence independently H or are        absent;    -   m, n and p are independently an integer comprised between 0 and        2;    -   m+n+p≧4;    -   R³ is NH₂, NHR¹⁰;    -   r¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   their optically active forms such as enantiomers, diastereomers        and their racemate forms, and pharmaceutically acceptable salts        thereof; with the proviso that R⁴, R⁶ and R⁸ are not all H at        the same time.

We have found that the derivatives (I), prepared according to theinvention, are useful agents for the treatment of disease states,disorders and pathological conditions wherein modulation of the A_(2A)receptor activity would result at improving the health of the patient.

An embodiment of this invention is that of compounds of formula I, foruse as medicaments.

In another embodiment, said medicament is used for treating a subjectaffected by motor disorders deriving from functional alterations in thebasal ganglia.

In a still further embodiment, said motor disorders consist of the onesinvolved in diseases comprising Parkinson's disease, Alzheimer'sdisease, Huntington's disease and Wilson's disease.

In another embodiment, the compounds of formula I are also useful forthe preparation of medicaments for the treatment of cerebral ischaemiaand/or associated with neurodegenerative processes.

The term “alkyl” refers to linear or branched alkyl groups having from 1to 6 carbon atoms. Preferred alkyl groups are exemplified by groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neo-butyl,tert-butyl, pentyl, iso-pentyl, n-hexyl and the like.

The term “alkenyl” refers to linear or branched alkenyl groupspreferably having from 2 to 12 carbon atoms, or preferably, 2 to 6carbon atoms also named “lower” alkenyl group and having at least 1 or 2sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl(—CH═CH2), propenyl (allyl, —CH₂CH═CH₂) and the like. The term alkenylembraces radicals having “cis” and “trans” orientation, or alternatively“Z” and “E”.

The term “cycloalkyl” refers to a saturated or partially unsaturated(i.e., not aromatic) carbocyclic group of from 3 to 10 carbon atomshaving a single ring or multiple condensed rings.

Examples of C₃-C₁₀ cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like.

The term “heterocycloalkyl” refers to a saturated or partiallyunsaturated (i.e., not aromatic) five-, six- or seven-membered ringcontaining one or more heteroatoms selected from the group consisting ofnitrogen, oxygen or sulfur atoms, and which rings may be substitutedwith lower alkyl, lower alkenyl, or aryl. Preferred heterocycloalkylinclude pyrrolidine, piperidine, piperazine, ketopiperazine,thiomorpholine, 2,5-diketopiprazine, 1-methylpiperazine, morpholine,dihydropyranyl, tetrahydropyranyl, tetrahydrofuran, dihydropyrrole,imidazolidine, dihydropyrazole, pyrazolidine and the like.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 14carbon atoms having a single ring (e. g., phenyl) or multiple rings thatmay be attached in a pendent manner or may be fused. Preferred arylinclude phenyl.

The term “alkoxy” refers to the group —O—R where R includes “C₁-C₆alkyl”, “C₂-C₆ alkenyl”, “C₃-C₁₀ cycloalkyl” and “heterocycloalkyl”.

The term “alkoxyalkyl” refers to alkyl groups as above defined having analkoxy substituent as above defined, including 2-ethoxyethyl,methoxymethyl and the like.

The term “amino” refers to the group —NRR′ where each R, R′ isindependently H, “alkyl”, “alkenyf”, “cycloalkyl”, “heterocycloalkyl”,“aryl”, “heteroaryl” and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3 to 8-memberedheterocycloalkyl ring as above defined. The term “aminoalkyl” or“amino(C₁-C₆)alkyl” refers to alkyl groups as above defined having anamino substituent as above defined.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below identified compounds of formula (I), that retainthe desired biological activity. Examples of such salts include, but arenot restricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,toluene sulfonic acid, naphthalene disulfonic acid, methanesulfonic acidand poly-galacturonic acid. When the salt is of a mono acid (forexample, the hydrochloride, the hydrobromide, the p-toluenesulphonate,or the acetate), the hydrogen form of a di-acid (for example, thehydrogen sulphate, or the succinate), or the dihydrogen form of atri-acid (for example, the dihydrogen phosphate, or the citrate), atleast one molar equivalent and usually a molar excess of the acid isemployed. However, when such salts as the sulphate, the hemisuccinate,the hydrogen phosphate, or the phosphate are desired, the appropriateand exact chemical equivalents of acid are generally used.

“Pharmaceutically active derivative” refers to any compound that uponadministration to the patient is capable of providing directly orindirectly, the activity disclosed herein.

The compounds according to formula I could be employed alone or incombination with further pharmaceutical agents such as L-DOPA.

The compounds of the present invention may be prepared from readilyavailable starting materials using the following general methods andprocedures. It will be appreciated that where typical or preferredexperimental conditions (i.e., reaction temperatures, time, moles ofreagents, solvents, etc.) are given, other experimental conditions canalso be used unless otherwise stated. Optimum reaction conditions mayvary with the particular reactants or solvents used, but such conditionscan be determined by one skilled in the art by routine optimisationprocedures.

When employed as pharmaceuticals, the compounds of the present inventionare typically administered in the form of a pharmaceutical composition.Hence, pharmaceutical compositions comprising a compound of formula (I)and a pharmaceutically acceptable carrier, diluent or excipienttherefore is also within the scope of the present invention. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound. A personskilled in the art is aware of a whole variety of such carrier, diluentor excipient compounds suitable to formulate a pharmaceuticalcomposition.

The compounds of the present invention, together with a conventionallyemployed adjuvant, carrier, diluent or excipient may be placed into theform of pharmaceutical compositions and unit dosages thereof, and suchforms may be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

Generally, the compounds of this invention are administered in a“pharmaceutically effective amount”. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,drug combination, the age, body weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.Generally, an effective dose will be from 0.01 mg/kg to 100 mg/kg,preferably 0.05 mg/kg to 50 mg/kg. Compositions may be administeredindividually to a patient or may be administered in combination withother agents, drugs or hormones. For any compound, the therapeuticallyeffective dose can be estimated initially either in cell culture assaysor in animal models, usually mice, rats, guinea pigs, rabbits, dogs, orpigs.

The animal model may also be used to determine the appropriateconcentration range and route of administration. Such information canthen be used to determine useful doses and routes for administration inhumans. In calculating the Human Equivalent Dose (HED) it is recommendedto use the conversion table provided by the FDA in Guidance for Industryand Reviewers document available from FDA. The pharmaceuticalcompositions of this invention can be administered by a variety ofroutes including oral, rectal, sublingual, transdermal, subcutaneous,intravenous, intramuscular, intrathecal, intraperitoneal, intranasal andlocally on the diseased tissue after surgical operation.

Depending on the intended route of delivery, the compounds arepreferably formulated as parenteral, topical or oral compositions. Thecompositions for oral administration may take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includerefilled, pre-measured ampoules or syringes of the liquid compositionsor pills, tablets, capsules or the like in the case of solidcompositions. In such compositions, the compound of the invention isusually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

Dosage treatment may be a single dose schedule or a multiple doseschedule. Liquid forms suitable for oral administration may include asuitable aqueous or non-aqueous vehicle with buffers, suspending anddispensing agents, colorants, flavours and the like.

Solid forms may include, for example, any of the following ingredients,or compounds of a similar nature: a binder such as microcrystallinecellulose, acacia, gum tragacanth, gelatine or polyvinyl-pyrrolidone; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, primogel, or potato or corn starch; a lubricant such asmagnesium stearate, talc, polyethylene glycol or silica; a glidant suchas colloidal silicon dioxide; a sweetening agent such as sucrose orsaccharin; or a flavoring agent such as peppermint, methyl salicylate,or orange flavoring. The tablets may be coated according to methods wellknown to people skilled in the art of pharmaceutical practice.

Parenteral compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable earners known inthe art. As mentioned above, the compound of formula I in suchcompositions is typically a minor component, frequently ranging between0.05 to 10% by weight with the remainder being the injectable carrierand the like.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

The above-described components for orally administered or parenteralcompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 5 of Remington'sPharmaceutical Sciences, 20th Edition, 2000, Mack Publishing Company,Easton, Pa., which is incorporated herein be reference.

A further embodiment of the invention is a process for the preparationof pharmaceutical compositions characterised by mixing one or morecompounds of formula (I) with suitable excipients, stabilizers and/orpharmaceutically acceptable diluents.

As above disclosed, the compounds of the present invention are useful asmedicaments due to their Aza modulating properties for the treatment ofdisorders where such modulation result in improving the health of thepatient. In particular, patients suffering from Parkinson's disease,Alzheimer's disease, Huntington's disease, Wilson's disease, psychiatricdisorders, Hallervorden-Spatz disease, progressive pallidal atrophy anddiabetes can be treated.

Objects of the present invention are pharmaceutical compositionscontaining compounds of formula I, as described earlier, in combinationwith excipients and/or pharmacologically acceptable diluents.

A further embodiment of the invention is a process for the preparationof compounds of formula I as defined above. The compounds of theinvention can be prepared by conventional synthetic methods and aredescribed underneath.

Method A

Compounds of formula (I), wherein

-   -   R¹═ is C₁-C₆ linear or branched alkyl;    -   R₂ is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴, R⁵, R⁷, and R⁹ are H;    -   R⁶ and R⁸ are at any occurrence independently H or hydroxyl with        at least one of them being hydroxyl;    -   m and p are independently an integer comprised between 0 and 2;    -   n is 1 or 2;    -   m+n+p≧4;    -   R³ is NH₂, NHR¹⁰; and    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the reaction of a        compound of formula II

-   -   wherein    -   R¹ is C₁-C₆ linear or branched alkyl;    -   R^(H) is N(R¹³)₂;    -   R¹³ is benzyl, p-(MeO)-benzyl, p-(Cl)-benzyl or p-(Br)-benzyl;    -   R¹² is Cl;    -   with a compound of formula III

R⁹—(CHR^(8a))_(p)—(CR^(6a)R⁷)_(m)—(CR⁴R⁵)_(n)—MgX   Formula III,

-   -   wherein,    -   X is Cl or Br;    -   R⁴, R⁵, R⁷, and R⁹ are H;    -   R^(6a) and R^(8a) are at any occurrence independently OH or H        with at least one of them being OH;    -   m and pare independently an integer comprised between 0 and 2;

n is 1 or 2;

-   -   m+n+p≧4;    -   in the presence of Fe(acac)₃ in an aprotic solvent such as THF        or NMP at a temperature ranging from 0° C. to RT.

Method B

Compounds of formula (I), wherein

-   -   R¹ is C₁-C₆ linear or branched alkyl;    -   R² is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴ and R⁵ are H;    -   R⁶ and R⁸ are at any occurrence independently H or ═O with the        meaning of carbonyl; with at least one of R⁶ and R⁸ being ═O        with the meaning of carbonyl;    -   R⁷ and R⁹ are at any occurrence independently H, or are absent        in case the corresponding carbon atom bearing said R⁶ or R⁸        group is involved in a carbonyl bond;    -   m and p are independently an integer comprised between 0 and 2;    -   n is 1 or 2;    -   m+n+p≧4;    -   R³ is NH₂, NHR¹⁰;    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₅)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the reaction of a        compound of formula II as defined above, with a compound of        formula IV

H—(CH₂)_(q)—(CR^(6b)R^(6c))_(r)—(CH₂)_(s)—MgX   Formula IV,

-   -   wherein    -   X is C¹ or Br;    -   R^(6b) and R^(6c) are at any occurrence independently both H or        when taken together with the carbon atom to which they are        attached to form a 1,3-dioxane group optionally substituted by        two or more methyl groups with at least one of the occurrence        being a 1,3-dioxane group substituted by two or more methyl        groups;    -   q is an integer comprised between 0 and 3;    -   r and s are independently an integer comprised between 1 and 3;        with q+r+s≧4; in the presence of a Fe(acac)₃ in an aprotic        solvent such as THF or NMP at a temperature ranging from 0° C.        to RT.

Method C

Compounds of formula (I), wherein

-   -   R¹ is C¹-C⁶ linear or branched alkyl;    -   R² is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n);    -   R⁴ is hydroxyl or ═O with the meaning of carbonyl;    -   R⁵ is H or is absent when R⁴ is =) with the meaning of carbonyl;    -   R⁶ and R⁸ are at any occurrence independently H, hydroxyl or ═O        with the meaning of carbonyl;    -   R⁷ and R⁹ are at any occurrence independently H or are absent in        case the corresponding carbon atom bearing said R⁶ or R⁸ group        is involved in a carbonyl bond;    -   n is 1;    -   m and p are independently an integer comprised between 1 and 2,        with m+p≧3;    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the following steps:        -   a) reaction of a compound of formula V

-   -   wherein R¹ is C₁-C₆ linear or branched alkyl;    -   with i-PrMgCl;        -   b) in situ addition of compound formula VI

H—(CHR^(8d))_(t)—(CR^(6d)R^(7d))_(s)—CHO Formula VI

-   -   wherein:    -   R^(6d) and R^(7d) are at any occurrence independently H or OH        with at least one of them being H; or    -   R^(6d) and R^(7d) when taken together with the carbon atom to        which they are attached, form a 1,3-dioxane group optionally        substituted by two or more methyl groups;    -   R^(8d) is H or hydroxyl;    -   s and t are independently an integer comprised between 1 and 2,        with s+t≧3;    -   in an aprotic solvent such as THF at a temperature ranging from        −78° C. to RT.

Method D

Compounds of formula (I), wherein

-   -   R¹═ is C₁-C₆ linear or branched alkyl;    -   R₂ is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴ and R⁵ are H;    -   R⁶ and R⁸ are at any occurrence independently H, hydroxyl or ═O        with the meaning of carbonyl;    -   R⁷ and R⁹ are at any occurrence independently H or are absent in        case the corresponding carbon atom bearing said R⁶ or R⁸ group        is involved in a carbonyl bond;    -   m and p are independently an integer comprised between 0 and 2;    -   n=2;    -   m+n+p≧4;    -   R³ is NH₂, NHR¹⁰;    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the reaction of a        compound of formula VII

-   -   wherein    -   R¹═ is C₁-C₆ linear or branched alkyl; with a compound of        formula VIII

-   -   wherein    -   R⁶ is at any occurrence independently H or hydroxyl,    -   u is an integer equal to or greater than 2;    -   in the presence of bis-triphenylphosphine palladium dichloride,        CuI and optionally a tertiary amine such as triethylamine in a        polar solvent such as dioxane at a temperature ranging from        0° C. to RT.

Method E

Compounds of formula (I), wherein

-   -   R¹═ is C₁-C₆ linear or branched alkyl;    -   R² is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴, R⁶ and R⁸ are at any occurrence independently H, hydroxyl or        ═O with the meaning of carbonyl;    -   R⁵, R⁷ and R⁹ are at any occurrence independently H or are        absent in case the corresponding carbon atom bearing said R⁴, R⁶        or R⁸ group is involved in a carbonyl bond;    -   m, n and p are independently an integer comprised between 0 and        2;    -   m+n+p≧4;    -   R³ is NH₂, NHR10;    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆) alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄        aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the reaction of        compounds of formula II as above described with a compound of        formula IX

-   -   wherein    -   R¹⁴ is at each occurrence independently H or OH;    -   R¹⁵ is H or OH;

v is ≧2;

-   -   in the presence of Hermann's catalyst and sodium acetate in a        polar solvent such as NMP.

Method F

Compounds of formula (I), wherein

-   -   R¹═ is C₁-C₆ linear or branched alkyl;    -   R2 is a group of formula R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n)—;    -   R⁴ and R⁵ are H;    -   R⁶ and R⁸ are at any occurrence independently H, hydroxyl or ═O        with the meaning of carbonyl;    -   R⁷ and R⁹ are at any occurrence independently H or are absent;    -   m and p are independently an integer comprised between 0 and 2;    -   n≧1;    -   m+n+p≧4;    -   R³ is NH₂, NHR¹⁰;    -   R¹⁰ is C₁-C₆ alkyl or C₁-C₆ hydroxyalkyl, C₁-C₃ alkoxyalkyl,        amino(C₁-C₆)alkyl, where the amino group is optionally        substituted with one or two C₁-C₃ alkyl groups, being said alkyl        groups linear or branched; C₆-C₁₄ aryl or C₆-C₁₄    -   aryl(C₁-C₆)alkyl, with the aryl group optionally substituted by        one or more substituents, either the same or different, selected        from the group constituted by halogen, hydroxy, C₁-C₆ alkoxy        linear or branched saturated or unsaturated, amino, mono- or        di-substituted with C₁-C₆ alkyl linear or branched;    -   can be synthesized by a process comprising the reaction of        compounds of formula VII as above described with a compound of        formula X

R⁹—(CHR⁸)_(p)—(CR^(6d)R^(7d))_(m)—(CR⁴R⁵)_(n)—ZnBr   Formula X;

wherein

-   -   R⁴ and R⁵ are H;    -   R^(6d) and R^(7d) are at any occurrence independently H or OH        with at least one of them being H; or    -   R^(6d) and R^(7d) when taken together with the carbon atom to        which they are attached, form a 1,3-dioxane group optionally        substituted by two or more methyl groups;    -   R⁸ is at any occurrence independently H or hydroxyl;    -   R⁹ is H;    -   m and p are independently an integer comprised between 0 and 2;    -   n≧1;    -   m+n+p≧4;    -   in a polar solvent such as THF.

In all said transformations, any interfering reactive group can beprotected and then deprotected according to well-established proceduresdescribed in organic chemistry (see for example: Greene T. W. and P. G.M. Wuts “Protective Groups in Organic Synthesis”, J. Wiley & Sons, Inc.,3rd Ed., 1999) and well known to those skilled in the art.

DESCRIPTION OF THE DRAWING

FIG. 1: it shows the efficacy of ST3932 at antagonizing thehaloperidol-induced catalepsy in mice.

FIG. 2: it shows the efficacy of ST4206 at increasing the number of 5contralateral rotation of 6-OHDA lesioned rats.

FIG. 3: it shows the efficacy of ST3829 at increasing the number ofcontralateral rotation of 6-OHDA lesioned rats.

FIG. 4: it shows the efficacy of ST3932 at increasing the number ofcontralateral rotation of 6-OHDA lesioned rats.

FIG. 5: it shows the efficacy of ST4206 at increasing the number ofcontralateral rotation of 6-OHDA lesioned rats.

EXAMPLES Abbreviations

AcOEt: ethyl acetate

atm: atmosphere

bs: broad singlet

DCM: dichloromethane

DMEM: Dulbecco's modified eagle's medium

DMSO: dimethylsyulfoxide

EDTA: ethylenediaminetetraacetic acid

Et₂O: diethyl ether

FBS: foetal Bovine Serum

MeOH: methanol

MgCl₂: magnesium dichloride

MS: mass spectrum

Na₂SO₄: sodium sulphate

NEt_(a): triethyl amine

NMP: N-methyl pyrrolidinone

PBS: phosphate-buffered saline

PCC: pyridinium chlorochromate

RP-HPLC: reversed phase-high-performance liquid chromatography

Rt: retention time

RT: room temperature

TfOH: Trifluoromethanesulfonic acid

General Remarks: ¹H spectra were recorded in CDCl₃ or DMSO-d₆ solutionas indicated, at 200 MHz with a Bruker instrument. The chemical shiftvalues are given in ppm and the coupling constants in Hz. Flash columnchromatography was carried out using silica gel (Merck 230-400 mesh).

Chiral chromatography was performed using a HPLC Shimadzu LC-10ASchromatograph connected with a Vis-UV SPD 10A Shimadzu detector and aShimadzu C-R6A chromatopak integrator. The stationary phase consisted ofa Chiralpak AD-H column, Daicel Chemical industries (Chiral France)[Amylose tris(3,5-dimethylphenylcarbamate) coated on 5 mm silica-gel] ofdiameter 0.46 cm, length 25 cm. The mobile phase consisted ofn-hexane/2-propanol: 9/1 at a flow equal to 1 ml/min, λ289 nm.

Example 1 4-(6-Amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol (ST4023) STEP A:4-(6-Chloro-9-methyl-9H-purin-2-yl)but-3-yn-1-ol

NEt₃ (4.9 ml, 34.5 mmol) and but-3-yn-1-ol (1.1 ml, 25.63 mmol) wereadded to a solution of 6-chloro-2-iodo-9-methyl-9H-purine (6.8 g, 23.3mmol), CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladiumdichloride (811 mg, 1.15 mmol) in dioxane (93 ml). The reaction mixturewas stirred at RT for 1 h. The solvents were removed under reducedpressure. Water (50 ml) was added to the dark residue obtained. Theaqueous phase was extracted with DCM (3×100 ml). The combined organicphases were dried over anhydrous sodium sulphate and evaporated underreduced pressure. The residue was purified by flash chromatography(DCM/MeOH: 94/6) to give an off-white precipitate.

Yield 77%.

¹H NMR (DMSO-d₆) δ: 2.67 (t, 2H, J=6.82 Hz), 3.68 (t, 2H, J=6.82 Hz),3.86 (s, 3H), 5.01 (bs, 1H), 8.68 (s, 1H).

¹³C NMR (DMSO-d₆) δ: 23.33, 30.63, 59.62, 80.55, 88.11, 130.42, 144.73,148.86, 149.28, 152.79

MS(ESI) m/e: 237-239 (M+H)+

STEP B: 4-(6-Amino-9-methyl-9H-purin-2-yl)but-3-yn-1-ol

To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-1-ol (650mg, 2.74 mmol) in dioxane (4 ml) was added 30% w/w water solution ofammonia (8 ml). The reaction mixture was stirred overnight in anautoclave at 70° C.

The solution was evaporated at atmospheric pressure at 50° C. to removethe ammonia. The reaction mixture was maintained at RT for 2 h, to givea white precipitate. The solid was filtered and dried under vacuum.

Yield 78%.

¹H NMR (DMSO-d₆) δ: 2.52 (t, 2H, J=6.82 Hz), 3.58 (dt, 2H, J=6.82 Hz,J=5.5 Hz), 3.68 (s, 3H), 4.90 (t, 1H, J=5.5 Hz), 7.25 (bs, 2H), 8.09 (s,1H).

¹³C NMR (DMSO-d₆) δ: 23.24, 29.84, 59.95, 82.23, 83.46, 118.51, 142.58,146.01, 150.38, 156.05

MS(ESI) m/e: 218 (M+H)⁺

STEP C: 4-(6-Amino-9-methyl-9H-purin-2-yl)butan-1-ol

To a solution of 4-(6-amino-9-methyl-9H-purin-2-yl)-but-3-yn-1-ol (1.5g, 6.88 mmol) in ethanol (30 ml) was added palladium 10% on graphite(1.35 g, 20% in weight). The mixture was stirred for 16 h in autoclaveat 50° C. under 4 atm of hydrogen. The catalyst was filtered through asmall pad of Celite and the solution obtained was evaporated underreduced pressure, to give a residue that was used for the followingreaction without further purification.

Yield 70%.

¹H NMR (DMSO-d₆) δ: 1.49 (m, 2H), 1.70 (m, 2H), 2.55 (t, 2H), 3.39 (m,2H), 3.67 (s, 3H), 4.34 (bs, 1H), 7.01 (s, 2H), 7.97 (s, 1H).

¹³C NMR (DMSO-d₆) δ: 25.54, 29.68, 32.85, 39.04, 61.09, 117.39, 141.33,151.04, 156.05, 164.93

MS(ESI) m/e: 222.0 (M+H)⁺

STEP D: 4-(6-Amino-8-bromo-9-methyl-9H-purin-2-yl)butan-1-ol

Bromine (0.4 ml, 6.8 mmol) was added dropwise, at −14° C., to4-(6-amino-9-methyl-9H-purin-2-yl)butan-1-ol (250 mg, 1.13 mmol)dissolved in a mixture of dioxane (5 ml) and acetate buffer pH 4 (2.5ml) (obtained by dissolving 4 g of sodium acetate in 100 ml of water andby adjusting to pH 4 with glacial acetic acid). The reaction was stirredat this temperature for 10 minutes and then at RT for 15 minutes. Excessof bromine was eliminated with sodium metabisulphite and the reactionbrought to pH 8 by addition of saturated solution of Na₂CO₃. The aqueousphase was extracted with DCM (6×10). The organic phases were dried overanhydrous sodium sulphate and evaporated under reduced pressure, to givea residue that was used for the following reaction without furtherpurification.

STEP E: 4-(6-Amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol (ST4023)

To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-1-ol(1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added Cs2CO3 (5.9 g,18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 ml, 17.2 mmol). Themixture was stirred overnight at 90° C. The solvent was evaporated underreduced pressure to give a residue that was purified by flashchromatography (DCM/MeOH: 93/7).

Yield 30%.

¹H NMR (DMSO-d₆) δ: 1.46 (m, 2H), 1.73 (m, 2H), 2.67 (t, 2H, J=7.5 Hz),3.38 (m, 2H), 3.76 (s, 3H), 4.38 (bs, 1H), 7.38 (s, 2H), 8,31 (s, 2H).

¹³C NMR (DMSO-d₆) δ: 25.43, 30.65, 32.80, 39.15, 61.04, 114.92, 138.06,141.42, 151.14, 156.17, 166.17

MS(ESI) m/e: 289 (M+H)⁺

Example 2 4-(6-Amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol (ST3932) STEP A:4-(6-Chloro-9-methyl-9H-purin-2-yl)but-3-yn-2-ol

To a solution of 6-chloro-2-iodo-9-methyl-9H -purine (6.8 g, 23.3 mmol),CuI (454 mg, 2.23 mmol) and bis-triphenylphosphine palladium dichloride(811 mg, 1.15 mmol) in dioxane (93 ml) were added triethylamine (4.9 ml,34.5 mmol) and but-3-yn-2-ol (1.1 ml, 25.63 mmol). The reaction mixturewas stirred at RT for 1 h. The volatiles were removed under reducedpressure. Water (50 ml) was added to the dark residue obtained. Theaqueous phase was extracted with DCM (3×100 ml). The combined organicphases were dried over anhydrous sodium sulphate and evaporated underreduced pressure. The combined organic phases were dried over anhydroussodium sulphate and evaporated under reduced pressure. The residue waspurified by flash chromatography (DCM/MeOH: 94/6).

Yield 77%.

¹H NMR (CDCl₃) δ: 1.62 (d, 3H, J=6.67 Hz), 3.95 (s, 3H), 4.81 (q, 1H,J=6.64), 8.17 (bs, 1H).

¹³C NMR (CDC₁₃) δ: 23.52, 29.72, 57.31, 81.41, 89.94, 130.59, 144.75,148.20, 149.21, 152.65.

MS(ESI) m/e: 237-239 (M+H)⁺

STEP B: 4-(6-Amino-9-methyl-9H-purin-2-yl)but-3-yn-2-ol

To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl) but-3-yn-2-ol (4.8g, 20.34 mmol) in dioxane (30 ml) was added 30% w/w water solution ofammonia (60 ml). The reaction mixture was stirred overnight in anautoclave at 70° C. The solution was evaporated at atmospheric pressureat 50° C. and then under reduced pressure. The residue was purified byflash chromatography (DCM/MeOH: 97/3).

Yield 78%.

1H NMR (DMSO-d₆) δ: 1.42 (d, 3H, J=6.67 Hz), 3.75 (s, 3H), 4.61 (q, 1H),5.71 (bs, 1H), 7.42 (bs, 2H) 8.17 (s, 1H).

13C NMR (DMSO-d6) δ: 24.75, 29.89, 56.83, 83.14, 87.63, 130.01, 142.74,145.65, 150.28, 156.07

MS(ESI) m/e: 218 (M+H)⁺

STEP C: 4-(6-Amino-9-methyl-9H-purin-2-yl)butan-2-ol

4-(6-Amino-9-methyl-9H -purin-2-yl)but-3-yn-2-ol (1.5 g, 6.88 mmol) wasplaced in an autoclave with ethanol (30 ml) and palladium 10% ongraphite (0.350 g, 20% in weight) was added. The mixture was stirredovernight under 4 atm of hydrogen at 50° C. The catalyst was filteredoff through Celite and the resulting solution was evaporated underreduced pressure, to give a residue that was used without any furtherpurification.

Yield 70%.

¹H NMR (CD₃OD) δ: 1.21 (d, 3H, J=6.32 Hz), 1.9 (m, 2H), 2.85 (m, 2H),3.35 (bs, 2H), 3.84 (s, 3H), 3.89 (m, 1H), 8.00 (s, 1H).

¹³C NMR (CD₃OD) δ: 22.01, 28.72, 34.97, 37.72, 66.89, 116.59, 141.54,150.37, 155.56, 165.42

MS(ESI) m/e: 222 (M+H)+

STEP D: 4-(6-Amino-8-bromo-9-methyl-9H-purin-2-yl)butan-2-ol

Bromine (2.1 ml, 41 mmol) was added dropwise at −14° C. to a solution of4-(6-amino-9-methyl-9H-purin-2-yl)butan-2-ol (800 mg, 3.60 mmol) in amixture of Me0H/THF (20 ml, 1/1) and acetate buffer pH=4 (10 ml). Thelatter was obtained dissolving 4 g of sodium acetate in 100 ml of waterand by adjusting to pH 4 through addition of glacial acetic acid. Thereaction was stirred at this temperature for 10 minutes and then at RTfor 10 minutes. Excess of bromine was quenched by addition of sodiummetabisulphite and the reaction was brought to pH 8 by addition of asaturated solution of Na₂CO₃. The organic solvents were evaporated underreduced pressure, to give a solid that was filtered and used without anyfurther purification.

Yield 76%.

STEP E: 4-(6-Amino-9-methyl-8-1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol (ST3932)

To a solution of 4-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)butan-2-ol(1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added C_(s)CO₃ (5.9 g,18.24 mmol) and 1H-1,2,3-triazole (1.2 g, 1.0 ml, 18.24 mmol). Themixture was stirred overnight at 90° C. The solvent was evaporated underreduced pressure to give a residue that was purified by flashchromatography (DCM/MeOH: 93/7).

Yield 27%.

¹H NMR (DMSO-d₆) δ: 1.09 (d, 3H, J=6.2 Hz), 1.78 (m, 2H), 2.72 (m, 2H),3.66 (m, 1H), 3.77 (s, 3H), 4.45 (bs, 1H), 7.32 (bs, 2H), 8.29 (s, 2H).

¹³C NMR (DMSO-d₆) δ: 24.0, 30.6, 35.9, 38.5, 66.2, 114.9, 138.0, 141.4,151.2, 156.2, 166.4

MS(ESI) m/e: 289 (M+H)⁺

Example 3 (S)-4-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H -purin-2-yl)butan-2-ol (ST5748)

This compound was prepared according to the procedure described inExample 2, using (S)-(−)-but-3-yn-2-ol in STEP 1 instead of itsracemate. In STEP E, the crude reaction mixture was purified by flashchromatography (DCM/MeOH: 95/5).

HPLC: Rt: 29 mn

Example 4 (R)-4-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H -purin-2-yl)butan-2-ol (ST5749)

This compound was prepared according to the procedure described inExample 2, using (R)-(−)-but-3-yn-2-ol in STEP 1 instead of itsracemate. In STEP E, the crude reaction mixture was first purified byflash chromatography (DCM/MeOH: 95/5).

HPLC: Rt: 26 mn

Example 5 1-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-l-ol (ST3829) STEP A:1-(6-Chloro-9-methyl-9H-purin-2-yl)butan-1-01

To a solution of 6-chloro-2-iodo-9-methyl-9H-purine (3.7 g, 12.6 mmol)in anhydrous THE (48 ml) at −78° C. under an atmosphere of nitrogen wasadded isopropylmagnesium chloride (8 ml, 15.12 mmol). After 30 minutesbutyraldehyde (1.7 ml, 16.38 mmol)was added at −78° C. dropwise. Thereaction mixture was stirred at −78° C. for 8 h and then allowed to warmto RT overnight. The reaction was quencend with a saturated solution ofNH₄Cl. The aqueous phase was extracted with DCM (three times). Theorganic phases were dried over anhydrous sodium sulphate and evaporatedunder reduced pressure. The residue was purified by flash chromatography(gradient DCM/MeOH: 98/2 to DCM/MeOH: 96/4).

Yield 59%.

¹H NMR (CD₃OD) δ: 0.96 (t, 3H, J=7.34), 1.45 (m, 2H), 1.86 (m, 2H), 3.95(s, 3H), 4.83 (t, 1H, J=6.5), 8.47 (s, 1H).

¹³C NMR (CD₃OD) δ: 12.85, 18.41, 29.22, 38.90, 73.80, 129.13, 147.46,149.6, 152.53, 166.27.

MS (ESI+): 241-243 (M+H)⁺

STEP B: 1-(6-Amino-9-methyl-9H-purin-2-yl)butan-1-ol

To the solution of 1-(6-chloro-9-methyl-9H-purin-2-yl)butan-1-ol (1.8 g,7.47 mmol) in dioxane (10 ml) was added 30% w/w water solution ofammonia (20 ml). The reaction mixture was stirred overnight in anautoclave at 70° C. The solution was evaporated at atmospheric pressureat 50° C. and then under reduced pressure. The residue was purified byflash chromatography (DCM/MeOH: 95/5).

Yield 80%.

¹H NMR (DMSO-d₆) δ: 0.93 (t, 3H, J=7.06), 1.40 (m, 2H), 1.78 (m, 2H),3.77 (s, 3H), 4.48 (m, 1H), 4.84 (d, 1H), 7.31 (s, 2H), 8.12 (s, 1H).

¹³C NMR (DMSO-d₆) δ: 14.95, 19.37, 30.29, 39.99, 73.86, 118.35, 142.33,151.18, 156.52, 166.43.

MS (ESI+): 222 (M+H)+

STEP C: 1-(6-Amino-8-bromo-9-methyl-9H-purin-2-yl)butan-1-ol

Bromine (3.6 ml, 70.4 mmol) was added dropwise, at −-14° C., to1-(6-amino-9-methyl-9H-purin-2-yl)butan-1-ol (1700 mg, 7.69 mmol)dissolved in a mixture of MeOH (20 ml), THF (20 ml) and acetate bufferpH 4 (20 ml) (obtained by dissolving 4 g of sodium acetate in 100 ml ofwater and by adjusting pH 4 with glacial acetic acid). The reaction wasstirred at this temperature for 15 minutes and then at RT for 10minutes. Excess of bromine was eliminated with sodium metabisulphite andthe reaction brought to pH 8 by addition of saturated solution ofNa₂CO₃. The organic solvents were evaporated under reduced pressure, togive a solid that was filtered and used for the following reactionwithout further purification.

Yield 82%.

STEP D:1-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol(ST3829)

To the solution of 1-(6-amino-8-bromo-9-methyl-9H-purin-2-yl)-butan-1-ol(1.4 g, 4.56 mmol) in anhydrous DMF (20 ml) were added C_(s)CO₃ (5.9 g,18.24 mmol) and then 1H-1,2,3-triazole (1.2 g, 1.0 m1,18.24 mmol). Themixture was stirred overnight at 90° C. The solvent was evaporated underreduced pressure to give a residue that was purified by flashchromatography (DCM/MeOH: 93/7).

Yield 30%.

¹H NMR (DMSO-d₆) δ: 0.92 (t, 3H, J=7.18), 1.40 (q, 2H, J=8.2), 1.75 (m,2H), 3.86 (s, 3H), 4.50 (m, 1H), 4.88 (d, 1H), 7.58 (bs, 1H), 8.37 (s,2H).

¹³C NMR (DMSO-d₆) δ: 14.94, 19.37, 31.34, 39.88, 74.06, 115.90, 138.63,142.27, 151.42, 156.64, 167.72.

MS (ESI+): 289(M+H)⁺

Example 61-(6-Amino-9-methyl-8-[1,2,3]triazol-2-14-9H-purin-2-1/1)-butan-1-oneST4208

MnO₂ (439mg, 5.04 mmol) was added to a solution of1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol(51mg, 0.2mmol) in DCM (4 ml) at RT. The resulting heterogeneoussolution was stirred overnight. After filtration over a celite pad, thesolvent was removed under reduced pressure to afford the desired productas a white powder.

Yield 40%.

¹H NMR (DMSO-d₆) δ: 8.4 (s, 2H), 7.7 (bs, 2H), 3.9 (s, 3H), 3.14 (t,2H), 1.66 (m, 2H), 0.95 (t, 3H)

ESI-MS (m/z): 287.1(M+H)⁺

Example 7 4-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one ST4206

Molecular sieves 4 Å(100 mg) and PCC (59 mg, 0.273 mmol) at 0° C. wereadded to a solution of4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-ol (25mg, 0.086 mmol) in DCM (1.2 ml). The mixture was stirred at RT for 1 hand then diluted with Et₂O at 0° C. and stirred for 30 minutes. Theresulting suspension was filtered through a celite pad. The filtrate wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (DCM to DCM/MeOH: 95/5) to afford a white powder.

Yield 37%.

¹H NMR (CD₃CN) δ: 8.1 (s, 2H), 5.9 (bs, 2H), 3.8 (s, 3H), 3.07 (t, 2H),2.9 (t, 2H), 2.2 (s, 3H).

ESI-MS (m/z): 287.1 (M+H)⁺

In alternative,4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one canbe prepared from an advanced intermediate obtained by a processinvolving Method B as above mentioned and as described underneath.

Preparation 1 4-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one (ST4206) STEP A:Dibenzyl-{9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}-amine

i) 1,2-dibromoethane (770 μl, 8.9 mmol) was added to a suspension of Mg(3.1 g, 127.5 mmol) in THF (75 ml) in inert atmosphere (Ar). Then, asolution of 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane (8.0 ml, 42.5mmol) and 1,2-dibromoethane (3.08 ml, 36 mmol) in THF (75 ml) was added,and after the exothermic reaction was completed, the resulting reactionmixture was heated to 50° C. for 1 h.

ii) Fe(acac)₃ (315 mg, 0.89 mmol) was added to a solution ofdibenzyl-(2-chloro-9-methyl-9H-purin-6-yl)-amine (3.24 g, 8.9 mmol) inTHF (115 ml) and NMP (28. 5 ml) and the resulting reaction mixture wasstirred at RT for 30 min. 140 ml of the freshly prepared reagentobtained from STEP A (i) were added to the reaction mixture and thestirring was maintained for 1 h. The solvent was removed under reducedpressure, and the crude reaction mixture was poured into water andextracted by means of AcOEt. The combined organic phases were washedwith brine and dried with Na.₂SO₄. After removal of the solvent underreduced pressure, the desired adduct was obtained quantitatively as abrown oil.

¹H NMR (CDCl₃) δ: 0.85 (s, 3H), 1.00 (s, 3H), 1.30 (s, 3H), 1.89-2.00(m, 2H), 2.85-2.91 (m, 2H), 3.47-3.61 (m, 4H), 3.80 (s, 3H), 4.91(brs,2H), 5.40(brs, 2H), 7.2-7.4 (m, 10H), 7.66 (s, 1H).

ESI-MS (m/z): 486 (M+H)⁺

STEP B: Dibenzyl-{8-bromo-9-methyl-2-[2-(2,5,5-trimethyl- 81,31]dioxan-2-yl)-ethyl]-9H-purin-6-yl}amine

Bromine (0.89 ml, 17.5 mmol) was added dropwise at 0° C. to a solutionofdibenzyl-{9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}amine(1.7 g, 3.50 mmol) in 20 ml of a mixture of MeOH/THF (1/1) and acetatebuffer pH=4 (10 ml). The latter was obtained dissolving 4 g of sodiumacetate in 100 ml of water and by adjusting to pH 4 through addition ofglacial acetic acid. The reaction was stirred at RT for two hours.Excess of bromine was quenched by addition of sodium metabisulphite andthe reaction was brought to pH 8 by addition of a saturated solution ofNa₂CO₃. The organic solvents were evaporated under reduced pressure, togive a solid that was filtered and used without any further purificationin the next step.

¹H NMR (CDCl₃) δ: 0.85 (s, 3H), 1.00 (s, 3H), 1.30 (s, 3H), 1.89-2.00(m, 2H), 2.82-2.89 (m, 2H), 3.47-3.61 (m, 4H), 3.75 (s, 3H), 4.91(bs,2H), 5.40(bs, 2H), 7.20-7.40 (m, 10H).

ESI-MS (m/z): 564-566 (M+H)⁺

STEP C:Dibenzyl-{9-methyl-8-[1,2,3]triazol-2-yl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}-amine

To a solution ofdibenzyl-{8-bromo-9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}amine(1.9 g, 3.50 mmol) in anhydrous DMF (20 ml) were added K₂CO₃ (0.72 g,5.2 mmol) followed by 1H-1,2,3-triazole (362 mg, 5.2 mmol). The mixturewas stirred overnight at 100° C. The solvent was evaporated underreduced pressure to give a residue that was purified by flashchromatography (DCM/MeOH: 93/7).

Yield 30%.

¹H NMR (CDCl3) δ: 0.85 (s, 3H), 1.00 (s, 3H), 1.30 (s, 3H), 1.89-2.00(m, 2H), 2.79-2.83 (m, 2H), 3.47-3.61 (m, 4H), 3.90 (s, 3H), 4.91(brs,2H), 5.40 (bs, 2H), 7.2-7.4 (m, 10H), 8.00 (s, 21-1).

MS(ESI) m/e: 553 (M+H)⁺

STEP D:4-(6-Amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one(ST4206)

The intermediate obtained form STEP C, was deprotected using standardTfOH conditions, which after chromatography on silica gel allowed theobtention of the desired adduct quantitatively.

¹H NMR (CD3CN) δ: 8.10 (s, 2H), 5.90 (bs, 2H), 3.80 (s, 3H), 3.07 (t,2H), 2.90 (t, 2H), 2.20 (s, 3H).

ESI-MS (m/z): 287 (M+H)⁺

In alternative,4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one canbe prepared from an advanced intermediate obtained by a processinvolving Method E as above mentioned and as described underneath.

Preparation 2

Hermann catalyst (8 mg, 0.008 mmol, 0.08 eq), Bu₄NBr (8 mg, 0.025 mmol,0.25 eq), NaOAc (9 mg, 0.11 mmol, 1.1 eq) and 3-buten-2-ol (13μl, 0.15mmol, 1.5 eq) were added to a solution of(2-chloro-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-yl)-bis-(4-methoxy-benzyl)-amine(49 mg, 0.10 mmol) in NMP (1 ml). The resulting reaction mixture washeated to 100° C. for 16 h and further Hermann catalyst, Bu₄NBr, andNaOAc were added in the same proportions together with further 3 eq of3-buten-2-ol. The stirring was continued for 22 h at 140° C. beforecooling to RT. The resulting crude suspension was diluted with AcOEt andthe solid was filtered off. The organic phase was washed with H₂O andthen dried over Na₂SO₄. Removal of the solvent under vacuo andpurification through preparative thin layer chromatography allowed theobtention as a white solid of the desired4-{6-[bis-(4-methoxy-benzyl)-amino]-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl}-butan-2-one.

Yield 42%.

¹H NMR (CDCl₃) δ: 2.12 (s, 3H), 2.94 (t, 2H), 3.16 (t, 2H), 3.78 (s,6H), 3.94 (s, 3H), 4.85 (bs, 2H), 5.39(bs, 2H), 6.82 (d, 4H), 7.18 (d,4H), 7.94 (s, 2H).

Biology

The compounds of the present invention were tested in a competitionbinding assay for their ability to inhibit A_(2a) receptor.

Example 8 A_(2a) Receptor Inhibition

Method

HEK293 Cell Culture and Membrane Preparation

HEK293 cells, stably expressing the human adenosine A_(2a), receptorgene (PerkinElmer, Boston, Mass., USA, cat. RBHA2AC), were grown inFalcon flasks in DMEM (Cambrex, Verviers, Belgium) supplemented with 10%FBS (Cambrex), 1 mmol/l sodium pyruvate (Sigma-Aldrich, Saint Louis,Mo., USA), 0.4 mg/ml G418 (Sigma-Aldrich) at 37° C. in a 5% CO₂atmosphere. For radioligand binding experiments, the cells werecollected at 80% of confluence, in 5 mmol/l Tris-HCl (Sigma-Aldrich), pH7.4, containing 2 mmol/l EDTA, counted, washed in PBS (Cambrex),resuspended in incubation buffer A containing 50 mmol/l Tris-HCl, pH7.4,10 mmol/l MgCl₂ (Sigma-Aldrich) and homogenized using an UltraTurrax T25. The membranes were centrifuged and homogenized once againand the final pellet was stored at −80° C. until use. Prior to thecompetition binding assay, the pellet was resuspended in buffer A at thedesired protein concentration and membrane suspension was incubated with2 U/ml adenosine deaminase (ADA, Sigma-Aldrich) for 30 min at 37 ° C. toremove endogenous adenosine.

Protein Concentration and Competition Binding Assay

The protein concentration of membrane suspension was determined usingthe Bradford method (Pierce, Rockford, Ill., USA) with bovine albumin asstandard. Competition binding experiments were performed by incubatingmembranes (5-10 μg of protein/sample) with a single concentration of theA_(2a) antagonist [³H]ZM241385 (Biotrend, Cologne, Germany) (2 nmol/l),in the presence of various concentrations (ranging from 10⁻⁵ to 10⁻¹¹mol/l) of test and reference compounds in 96-well filter plates(MultiScreen system, cat. MAFBNOB10, Millipore, Billerica, Mass., USA)for one h at 4 ° C. in a total volume of 200μl/well of appropriatebuffer (50 mmol/l Tris-HCl, pH 7.4, 10 mmol/l MgCl₂). Nonspecificbinding was determined in the presence of 10 μmol/l cold ZM241385(Tocris, Ellisville, Mo., USA). At the end of incubation, bound and freeradioligands were separated by filtering the 96-well filter plates usinga Millipore filtration apparatus (MultiScreenHTS vacuum manifold).Filter plates were then washed several times with ice-cold buffer (50mmol/l Tris-HCl, pH 7.4) and filter-bound radioactivity measured using aMicroBeta counter (PerkinElmer) after addition of 30 μl/well ofOptiPhase SuperMix scintillation cocktail (PerkinElmer). Fourexperiments were performed in triplicate by JANUS® automated workstation(Perkin Elmer).

Data were analyzed by nonlinear regression analysis with GraphPad PRISMcommercial software and expressed as IC₅₀, defined as the concentrationof compounds that inhibits 50% of [³H]ZM241385 binding. Inhibitorybinding constant (Ki) values were calculated from IC₅₀ values accordingto the Cheng and Prusoff equation Ki=IC₅₀/(1+[C]/K_(d)), where [C] isthe concentration of the radioligand and K_(d) its dissociationconstant.

Results

All tested compounds proved to be highly active in binding A2A receptorassay (table 1).

TABLE 1 A_(2A) Examples Ki nM 1 53 2 8 3 19 4 8 5 22 6 19 7 12

Example 9

A1 receptor inhibition

Method

Competition binding experiments have been performed incubating membranesfrom CHO-K1 cells stably transfected with the human adenosine Alreceptor (cat. ES-010-M400UA, Perkin Elmer, Boston, Mass., USA) (5-10 μgof protein/sample) with a single concentration of [3H]DPCPX (1.7 nmol/l)(Perkin Elmer), in the presence of various concentrations (ranging from10⁻⁵ to 10 ⁻¹⁰ M) of cold DPCPX, ST4206 and ST4208 in 96-well filterplates (MultiScreen system, cat #MAFBNOB10, Millipore, Billerica, Mass.,USA) for 60 min at 25° C. in a total volume of 200 μL/well of 25 mmol/lHepes, 5 mmol/l MgCl₂, 1 mmol/l CaCl₂, 100 mmol/L NaCl, pH 7.4 (all fromSigma-Aldrich). Non-specific binding has been determined in the presenceof 250 μmol/l of cold DPCPX (8-cyclopentyl-1,3-dipropylxanthine,Sigma-Aldrich). At the end of incubation, bound and free radioligandshave been separated by filtering the 96-well filter plates using aMillipore filtration apparatus (MultiscreenHTS vacuum manifold). Filterplates have been washed several times with ice-cold buffer (50 mmol/lTris-HCl, pH 7.4) and filter-bound radioactivity measured using aMicroBeta counter (PerkinElmer) after addition of 30 μL/well ofOptiPhase SuperMix scintillation cocktail (PerkinElmer).

Data have been analyzed using nonlinear regression with GraphPad PRISMcommercial software. Data will be expressed as test compoundconcentration causing a half maximal inhibition of control values(IC₅₀). Inhibitory binding constant (Ki) values will be calculated fromIC₅₀ values, according to the Cheng and Prusoff equationK_(i)=IC₅₀/(1+[C]/K_(d)), where [C] is the concentration of theradioligand and K_(d) its dissociation constant.

Results

Tested compounds bound A₁ adenosine receptors with the Ki valuesreported in Table 2.

TABLE 2 A₁ Examples Ki nM 1 51 2 27 5 120 6 216 7 197

Example 10

cAMP Inhibition

The compounds of the present invention were tested to assess theircapacity to inhibit cAMP accumulation induced by the A_(2A) agonist5′-N-ethylcarboxamidoadenosine (NECA).

Methods

cAMP quantitative determination was performed with an enzyme immunoassaysystem (cat. RPN2255, Amersham Biosciences) according to manufacturer'sinstructions. HEK 293 cells, stably expressing the human adenosineA_(2a), receptor gene (PerkinElmer, Boston, Mass., USA, cat. RBHA2AC),were grown in Falcon flasks in DMEM (Cambrex, Verviers, Belgium)supplemented with 10% FBS (Cambrex), 1 mmol/1 sodium pyruvate(Sigma-Aldrich, St. Louis, Mo., USA), and 0.4 mg/ml G418 (Sigma-Aldrich)at 37° C. in a 5% CO₂ atmosphere. Cells were plated on 96-well dishes ata concentration of 10³ cells/well 48 hours before test compoundexposure. Before cell stimulation with the compounds, cells were treatedfor 10 min at 37° C. with 0.5 mmol/l of the phosphodiesterase inhibitorRo 20-1724 (Sigma-Aldrich) and with 2 U/ml of adenosine deaminase (ADA,Sigma-Aldrich). Medium was then changed with fresh medium containingscalar concentrations of test compounds (10⁻¹⁰-10⁻⁴ mol/l) at 37° C.and, after 10 min, 100 nmol/l NECA was added cAMP was extracted 20 minafter and quantified.

Data were analyzed by nonlinear regression analysis with GraphPad PRISMcommercial software. Test compound concentrations causing a half maximalinhibition of control values (IC₅₀ calculated by GraphPad Prismsoftware) was reported (mean±SEM of four independent experiments).

Results

All compounds resulted efficacious at inhibiting agonist-induced cAMPaccumulation (table 3) and behaved as expected for A_(2a) receptorantagonists.

TABLE 3 cAMP Examples IC₅₀ μM 1 2.12 2 0.45 3 0.26 4 0.42 5 2.32 6 2.927 0.99

Example 11

In order to evaluate the selectivity profile of the compounds of thepresent invention, three of them (ST3829, ST3932 and ST4023) were alsocharacterized for their affinity toward a battery of 51 differentreceptors. The majority of the 51 assays were human recombinantreceptors of the following types: adenosine, adrenergic, cannabinoid,dopamine, GABA, histamine, melatonin, muscarinic, prostanoid andserotonin receptors belonging to non peptide receptors family;angiotensin-II, bradychinin, chemokines, cholecistokinin, endothelin,galanin, melacortin, neurokinin, neuropeptide Y, neurotensin, opioid andopioid like, somatostatin, vasoactive intestinal peptide and vasopressinreceptors belonging to peptide receptors family; Ca²⁺ channel, K⁺channel and Nachannel belonging to the ion channel family and dopamine,norepinephrine and serotonin belonging to the amine transportersreceptors family. These three compounds were tested at a concentrationof 10μM. Interestingly, none of them demonstrated any substantialaffinity toward any of the above-mentioned receptors.

Example 12 Haloperidol-Induced Catalepsy Mice Model

ST3829, ST3932 and ST4023 were tested to assess their capacity toantagonize haloperidol-induced catalepsy in mice.

Methods

Haloperidol (2 mg/kg) was injected i.p. to CD1 mice 2.5 h before oraladministration of ST3932 or ST4206. The latter were administered atdoses of 10, 20 or 40 mg/kg.

Then, each CD1 mouse was gently placed by its forepaws on a wire at aheight of 4.5 cm. Catalepsy was measured as the time (expressed inseconds) necessary for the animal to step down with at least oneforepaw, with an end point of 60 seconds, time after which the mouse wasgently removed from the wire. Then, catalepsy was scored every 60 minfor seven h.

Data Evaluation

All data were expressed both as individual and mean values, plus orminus standard error (Mean±SEM) of catalepsy time in seconds.Statistical analysis was performed using sigma stat program. Aftercalculation of AUC throughout 7 hours, the one-way ANOVA followed byDunnett's test were used. Basal time was not considered statisticallybecause this time-point was only used to check that catalepsy wassuccessfully induced in all animals.

Results

Both ST3932 and ST4206 significantly antagonized haloperidol-inducedcatalepsy in a dose-dependent manner (FIGS. 1 and 2).

Example 13 Enhancement of L-DOPA Antiparkinsonian Activity

Rats (Sprague Dawley) under chloral hydrate (400 mg/kg) anaesthesia wereplaced in a Kopf stereotaxic apparatus. Through a stainless steelcannula, 6-OHDA was injected at a rate of 1 μl/min into the left medialforebrain bundle at coordinates A=−2.2, L=+1.5 and V=−7.8, according tothe Pellegrino atlas. All rats, including shams, were treated withdesipramine (10 mg/kg) 10 min before anaesthesia to prevent damage tonoradrenergic neurons.

Two weeks after the 6-OHDA injection, all animals were tested for theircontra lateral rotation capacity in response to 30 mg/kg i.p.benserazide followed by 50 mg/kg i.p. of L-Dopa 30 min later. Rats notshowing at least 200 contra lateral rotations within the 3 h testingperiod were eliminated from the study. One week after this test,selected animals were randomized to be enrolled in three studies. Eachstudy involved seven groups of eight animals.

Tested compounds (ST3829, ST3932 and ST4206) were dissolved in asolution containing 10% sucrose and 0.3% Tween 80 in sterile water inorder to obtain three different dosage forms (i.e., 10, 20 and 40mg/kg).

Group 1 Tested compound 10 mg/kg Group 2 Tested compound 20 mg/kg Group3 Tested compound 40 mg/kg Group 4 6 mg benserazide + 3 mg L-DOPA Group5 Tested compound 10 mg/kg and 6 mg benserazide + 3 mg L-DOPA Group 6Tested compound 20 mg/kg and 6 mg benserazide + 3 mg L-DOPA Group 7Tested compound 40 mg/kg and 6 mg benserazide + 3 mg L-DOPA

In groups 5, 6 and 7 benserazide was administered first, followed by thetested compound 25 min after and finally by L-DOPA 5 min later.

Results

In the 6-OHDA rat model of Parkinson's disease, adenosine A2a receptorantagonists increase turning behaviour induced by L-Dopa showingantiparkinsonian effects. In this study it was shown that ST3932 andST4206, administered to rats with a threshold dose of L-Dopa, increasedthe contralateral turning behaviour induced by L-Dopa displaying amarked antiparkinsonian activity.

1-15. (canceled)
 16. A compound having the general formula I

R¹ is C₁-C₆ linear or branched alkyl; R² is a group of formula:R⁹—(CHR⁸)_(p)—(CR⁶R⁷)_(m)—(CR⁴R⁵)_(n); R⁴, R⁶ and R⁸ are independentlyH, hydroxyl or ═O with the meaning of carbonyl; R⁵, R⁷ and R⁹ areindependently H or are absent; m, n and p are independently an integercomprised between 0 and 2; m+n+p≧4; R³ is NH₂ or NHR¹⁰; R¹⁰ is linear orbranched C₁-C₆ alkyl; linear or branched C₁-C₆ hydroxyalkyl; linear orbranched (C₁-C₃)alkoxy(C₁-C₆)alkyl; amino(C₁-C₆)alkyl, where the aminogroup is optionally substituted with one or two linear or branched C₁-C₃alkyl groups; C₆-C₁₄ aryl; or C₆-C₁₄ aryl(C₁-C₆)alkyl, wherein saidC₆-C₁₄ aryl group is optionally substituted by one or more substituents,which are the same or different, selected from the group consisting ofhalogen; hydroxyl; linear or branched, saturated or unsaturated C₁-C₆alkoxy; and amino, where the amino group is optionally substituted withone or two linear or branched C₁-C₆ alkyl groups; or an optically activeform, or pharmaceutically acceptable salt thereof; with the proviso thatR⁴, R⁶ and R⁸ are not all H at the same time.
 17. The compound accordingto claim 16 wherein n=2, m=1 and p≧1.
 18. The compound according toclaim 16, wherein R⁶ is OH or =0 with the meaning of carbonyl.
 19. Thecompound according to claim 16 wherein n=1 and R⁴ is OH or ═O with themeaning of carbonyl.
 20. The compound according to claim 16 which is4-(6-amino-9-methyl-8 [1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol,1-(6-amino-9-methyl-8 [1,2,3 ]triazol-2-yl-9H-purin-2-yl)butan-1-ol,4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one,4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl) butan-2-ol, or1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-1-one ora pharmaceutically acceptable salt thereof.
 21. The compound of claim 16which is 4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-one or a pharmaceutically acceptable salt thereof.
 22. Apharmaceutical composition comprising at least one compound according toclaim 16 or an optically active form, or a pharmaceutically acceptablesalt thereof and at least one pharmaceutically acceptable vehicle and/orexcipient.
 23. The pharmaceutical composition according to claim 22wherein the compound is4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol,1-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol,4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one,4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol, or1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-1-one ora pharmaceutically acceptable salt thereof.
 24. The pharmaceuticalcomposition according to claim 22 which further comprises L-DOPA.
 25. Aprocess for preparing a pharmaceutical composition comprising mixing atleast one compound according to claim 16 or an optically active form, ora pharmaceutically acceptable salt thereof with at least onepharmaceutically acceptable vehicle and/or excipient.
 26. A method fortreating a pathological state for which the modulation of A_(2A)activity would result at improving the health of a patient whichcomprises administering an effective amount of compound according toclaim 16 or an optically active form, or a pharmaceutically acceptablesalt thereof to a patient in need thereof.
 27. The method according toclaims 26 wherein the pathological state is a motor disorder.
 28. Themethod according to claim 27, wherein said motor disorder is Parkinson'sdisease, Alzheimer's disease, Huntington's disease, Wilson's disease orHallervorden-Spatz disease.
 29. The method according to claim 26 whereinsaid pathological state is cerebral ischaemia optionally associated withneurodegenerative processes.
 30. A method for treating Parkinson'sdisease which comprises administering an effective amount of thepharmaceutical composition according to claim 24 to a patient in needthereof.
 31. A process for synthesizing a compound of claim 16, whichcomprises reacting a compound of the formula II

wherein R¹ is C₁-C₆ linear or branched alkyl; _(R)11 is N(_(R) ¹³)₂; R¹³is benzyl, p-(Me0)-benzyl, p-(C1)-benzyl or p-(Br)-benzyl; R¹² is Cl;with a compound of formula IX

wherein R¹⁴ and R¹⁵ are at each occurrence independently H or OH; V is 2or 3; in the presence of Hermann's catalyst and sodium acetate in apolar solvent.